Hypoxic hUCMSC-derived extracellular vesicles attenuate allergic airway inflammation and airway remodeling in chronic asthma mice.
Hypoxic hUCMSC-derived extracellular vesicles attenuate allergic airway inflammation and airway remodeling in chronic asthma mice.
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缺氧 hUCMSC 来源的细胞外囊泡减轻慢性哮喘小鼠的过敏性气道炎症和气道重塑
DOI：
10.1186/s13287-020-02072-0
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发表时间：
2021-01-06
影响因子：
7.5
通讯作者：
Mao C
中科院分区：
文献类型：
--
作者：
Dong L;Wang Y;Zheng T;Pu Y;Ma Y;Qi X;Zhang W;Xue F;Shan Z;Liu J;Wang X;Mao C
作为间充质干细胞(MSCs)的主要功能形式之一，MSC来源的细胞外小泡(MSC-EVS)在过敏性哮喘的实验模型中显示出另一种治疗选择。氧浓度在MSCs的自我更新、增殖和EV释放中起着重要作用，最近的一项研究发现，在低氧条件下培养MSCs可以增强其抗哮喘作用。然而，低氧间充质干细胞来源的EVS(Hypo-EVS)在哮喘中的潜力仍不清楚。用卵白蛋白(OVA)致敏和激发BALB/c雌性小鼠，每组每周接受PBS、常氧人脐带MSC-EVS(NOR-EVS)或Hypo-EVS。治疗结束后，安乐死动物，收集肺和支气管肺泡灌洗液(BALF)。采用苏木精-伊红(HE)染色、高碘酸席夫(PAS)染色和Masson‘s三色染色、酶联免疫吸附试验(EL ISA)、Western印迹分析和实时荧光定量聚合酶链式反应(Real-Time-PCR)等方法，观察大鼠呼吸道和肺实质炎症反应和胶原纤维含量。低氧环境可促进人脐血间充质干细胞(HUCMSCs)释放更多EV。在OVA动物中，给予NOR-EVS或Hypo-EVS显著改善哮喘小鼠的BALF总细胞、嗜酸性粒细胞和促炎介质(IL-4和IL-13)。此外，在抑制哮喘小鼠的呼吸道炎症方面，低水平EVS通常比NOR-EVS更有效。与NOR-EVS相比，Hypo-EVS进一步预防小鼠慢性变态反应性气道重塑，并伴随促纤维化标志物α-SMA、胶原-1和α-Smad2/3信号通路的表达减少。在体外，异型EVS可降低α-β-1刺激的人肺成纤维细胞中p-Smad2/3、SmA-SMA和胶原-1的表达。此外，我们还发现异型EVS中miR-146a-5p的表达比NOR-EVS中的表达丰富，并且Hypo-EV给药对哮喘小鼠肺组织和经β-β1处理的HLF-1中miR-146a-5p的表达均无影响。更重要的是，在低EV中miR-146a-5p的表达减少削弱了Hypo-EV介导的OVA小鼠的肺保护。我们的发现提供了第一个证据，表明低氧hUCMSC来源的EVS可以减轻慢性哮喘小鼠的过敏性气道炎症和气道重塑，可能为哮喘的治疗创造新的途径。
As one of the main functional forms of mesenchymal stem cells (MSCs), MSC-derived extracellular vesicles (MSC-EVs) have shown an alternative therapeutic option in experimental models of allergic asthma. Oxygen concentration plays an important role in the self-renewal, proliferation, and EV release of MSCs and a recent study found that the anti-asthma effect of MSCs was enhanced by culture in hypoxic conditions. However, the potential of hypoxic MSC-derived EVs (Hypo-EVs) in asthma is still unknown. BALB/c female mice were sensitized and challenged with ovalbumin (OVA), and each group received PBS, normoxic human umbilical cord MSC-EVs (Nor-EVs), or Hypo-EVs weekly. After treatment, the animals were euthanized, and their lungs and bronchoalveolar lavage fluid (BALF) were collected. With the use of hematoxylin and eosin (HE), periodic acid-Schiff (PAS) and Masson’s trichrome staining, enzyme-linked immune sorbent assay (ELISA), Western blot analysis, and real-time PCR, the inflammation and collagen fiber content of airways and lung parenchyma were investigated. Hypoxic environment can promote human umbilical cord MSCs (hUCMSCs) to release more EVs. In OVA animals, the administration of Nor-EVs or Hypo-EVs significantly ameliorated the BALF total cells, eosinophils, and pro-inflammatory mediators (IL-4 and IL-13) in asthmatic mice. Moreover, Hypo-EVs were generally more potent than Nor-EVs in suppressing airway inflammation in asthmatic mice. Compared with Nor-EVs, Hypo-EVs further prevented mouse chronic allergic airway remodeling, concomitant with the decreased expression of pro-fibrogenic markers α-smooth muscle actin (α-SMA), collagen-1, and TGF-β1-p-smad2/3 signaling pathway. In vitro, Hypo-EVs decreased the expression of p-smad2/3, α-SMA, and collagen-1 in HLF-1 cells (human lung fibroblasts) stimulated by TGF-β1. In addition, we showed that miR-146a-5p was enriched in Hypo-EVs compared with that in Nor-EVs, and Hypo-EV administration unregulated the miR-146a-5p expression both in asthma mice lung tissues and in TGF-β1-treated HLF-1. More importantly, decreased miR-146a-5p expression in Hypo-EVs impaired Hypo-EV-mediated lung protection in OVA mice. Our findings provided the first evidence that hypoxic hUCMSC-derived EVs attenuated allergic airway inflammation and airway remodeling in chronic asthma mice, potentially creating new avenues for the treatment of asthma.
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影响因子：
3.3
作者：
Ding, Dah-Ching;Chang, Yu-Hsun;Lin, Shinn-Zong
通讯作者：
Lin, Shinn-Zong
DOI：
10.33594/000000102
发表时间：
2019-01-01
期刊：
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology
影响因子：
--
作者：
Collino, Federica;Lopes, Jarlene Alecia;Lindoso, Rafael Soares
通讯作者：
Lindoso, Rafael Soares
影响因子：
3.7
作者：
Gangadaran, Prakash;Rajendran, Ramya Lakshmi;Ahn, Byeong-Cheol
通讯作者：
Ahn, Byeong-Cheol
来自缺氧处理的人脂肪间充质干细胞的外泌体通过 VEGF/VEGF-R 增强血管生成
DOI：
10.1016/j.biocel.2019.01.017
发表时间：
2019-04-01
影响因子：
4
作者：
Han, Yudi;Ren, Jing;Han, Yan
通讯作者：
Han, Yan
DOI：
10.1165/rcmb.2003-0063oc
发表时间：
2003-09-01
影响因子：
6.4
作者：
Hu, B;Wu, Z;Phan, SH
通讯作者：
Phan, SH